Transcranial magnetic stimulation of the prefrontal cortex in awake nonhuman primates evokes a polysynaptic neck muscle response that reflects oculomotor activity at the time of stimulation.

Transcranial magnetic stimulation (TMS) has emerged as an important technique in cognitive neuroscience, permitting causal inferences about the contribution of a given brain area to behavior. Despite widespread use, exactly how TMS influences neural activity throughout an interconnected network, and how such influences ultimately change behavior, remain unclear. The oculomotor system of nonhuman primates (NHPs) offers a potential animal model to bridge this gap. Here, based on results suggesting that neck muscle activity provides a sensitive indicator of oculomotor activation, we show that single pulses of TMS over the frontal eye fields (FEFs) in awake NHPs evoked rapid (within ∼25 ms) and fairly consistent (∼50-75% of all trials) expression of a contralateral head-turning synergy. This neck muscle response resembled that evoked by subsaccadic electrical microstimulation of the FEF. Systematic variation in TMS location revealed that this response could also be evoked from the dorsolateral prefrontal cortex (dlPFC). Combining TMS with an oculomotor task revealed state dependency, with TMS evoking larger neck muscle responses when the stimulated area was actively engaged. Together, these results advance the suitability of the NHP oculomotor system as an animal model for TMS. The polysynaptic neck muscle response evoked by TMS of the prefrontal cortex is a quantifiable trial-by-trial reflection of oculomotor activation, comparable to the monosynaptic motor-evoked potential evoked by TMS of primary motor cortex. Our results also speak to a role for both the FEF and dlPFC in head orienting, presumably via subcortical connections with the superior colliculus

Overt responses during covert orienting.

A distributed network of cortical and subcortical brain areas controls our oculomotor behavior. This network includes the superior colliculus (SC), which coordinates an ancient visual grasp reflex via outputs that ramify widely within the brainstem and spinal cord, accessing saccadic and other premotor and autonomic circuits. In this Review, we discuss recent results correlating subliminal SC activity in the absence of saccades with diverse components of the visual grasp reflex, including neck and limb muscle recruitment, pupil dilation, and microsaccade propensity. Such subtle manifestations of covert orienting are accessible in the motor periphery and may provide the next generation of oculomotor biomarkers in health and disease

Transient Pupil Dilation after Subsaccadic Microstimulation of Primate Frontal Eye Fields.

UNLABELLED: Pupillometry provides a simple and noninvasive index for a variety of cognitive processes, including perception, attention, task consolidation, learning, and memory. The neural substrates by which such cognitive processes influence pupil diameter remain somewhat unclear, although cortical inputs to the locus coeruleus mediating arousal are likely involved. Changes in pupil diameter also accompany covert orienting; hence the oculomotor system may provide an alternative substrate for cognitive influences on pupil diameter. Here, we show that low-level electrical microstimulation of the primate frontal eye fields (FEFs), a cortical component of the oculomotor system strongly connected to the intermediate layers of the superior colliculus (SCi), evoked robust pupil dilation even in the absence of evoked saccades. The magnitude of such dilation scaled with increases in stimulation parameters, depending strongly on the intensity and number of pulses. Although there are multiple pathways by which FEF stimulation could cause pupil dilation, the timing and profile of dilation closely resembled that evoked by SCi stimulation. Moreover, pupil dilation evoked from the FEFs increased when presumed oculomotor activity was higher at the time of stimulation. Our findings implicate the oculomotor system as a potential substrate for how cognitive processes can influence pupil diameter. We suggest that a pathway from the frontal cortex through the SCi operates in parallel with frontal inputs to arousal circuits to regulate task-dependent modulation of pupil diameter, perhaps indicative of an organization wherein one pathway assumes primacy for a given cognitive process. SIGNIFICANCE STATEMENT: Pupillometry (the measurement of pupil diameter) provides a simple and noninvasive index for a variety of cognitive processes, offering a biomarker that has value in both health and disease. But how do cognitive processes influence pupil diameter? Here, we show that low-level stimulation of the primate frontal eye fields can induce robust pupil dilation without saccades. Pupil dilation scaled with the number and intensity of stimulation pulses and varied with endogenous oculomotor activity at the time of stimulation. The oculomotor system therefore provides a plausible pathway by which cognitive processes may influence pupil diameter, perhaps operating in conjunction with systems regulating arousal

Dorsal Neck Muscle Vibration Induces Upward Shifts in the Endpoints of Memory-Guided Saccades in Monkeys

Producing a movement in response to a sensory stimulus requires knowledge of the body's current configuration, and spindle organs embedded within muscles are a primary source of such kinesthetic information. Here, we sought to develop an animal model of kinesthetic illusions induced by mechanically vibrating muscles as a first step toward a mechanistic understanding of how kinesthesia is integrated into neural plans for action. We elected to examine the effects of mechanical vibration of dorsal neck muscles in head-restrained monkeys performing memory-guided saccades requiring them to look to the remembered location of a flashed target only after an imposed delay. During the delay on one-half of all trials, mechanical vibration (usually 1,500 ms in duration, 200 μm in amplitude, 100 Hz in frequency) was applied to the dorsal aspect on one side of the monkey's neck. We compared the metrics of such vibration saccades to control saccades without vibration during the delay interval. Relative to control saccades, the endpoints of vibration saccades were shifted consistently upward, even though the variability in saccadic endpoints was unaltered. Although the stability of the eye was compromised during the delay interval of vibration trials, as evidenced by an increased incidence of upward drifts and downward microsaccades, vibration saccades displayed different metrics than control saccades, including an upwardly deviated radial direction and increased vertical amplitude. The influence of variations in the duration (500–2,500 ms), amplitude (100–300 μm), or frequency (75–125 Hz) of vibration scaled well with the presumed change in spindle activity entrained by vibration. Comparisons of the profile of these results are made to the human literature. We conclude that neck muscle vibration induces alterations in oculomotor performance in monkeys consistent with a central interpretation of illusory neck flexion and downward gaze deviation due to increased activation in the spindles of neck extensor muscles

Dynamic and opposing adjustment of movement cancellation and generation in an oculomotor countermanding task.

Adaptive adjustments of strategies help optimize behavior in a dynamic and uncertain world. Previous studies in the countermanding (or stop-signal) paradigm have detailed how reaction times (RTs) change with trial sequence, demonstrating adaptive control of movement generation. Comparatively little is known about the adaptive control of movement cancellation in the countermanding task, mainly because movement cancellation implies the absence of an outcome and estimates of movement cancellation require hundreds of trials. Here, we exploit a within-trial proxy of movement cancellation based on recordings of neck muscle activity while human subjects attempted to cancel large eye-head gaze shifts. On a subset of successfully cancelled trials where gaze remains stable, small head-only movements to the target are actively braked by a pulse of antagonist neck muscle activity. The timing of such antagonist muscle recruitment relative to the stop signal, termed the antagonist latency, tended to decrease or increase after trials with or without a stop-signal, respectively. Over multiple time scales, fluctuations in the antagonist latency tended to be the mirror opposite of those occurring contemporaneously with RTs. These results provide new insights into the adaptive control of movement cancellation at an unprecedented resolution, suggesting it can be as prone to dynamic adjustment as movement generation. Adaptive control in the countermanding task appears to be governed by a dynamic balance between movement cancellation and generation: shifting the balance in favor of movement cancellation slows movement generation, whereas shifting the balance in favor of movement generation slows movement cancellation

Bilateral saccadic deficits following large and reversible inactivation of unilateral frontal eye field.

Inactivation permits direct assessment of the functional contribution of a given brain area to behavior. Previous inactivation studies of the frontal eye field (FEF) have either used large permanent ablations or reversible pharmacological techniques that only inactivate a small volume of tissue. Here we evaluated the impact of large, yet reversible, FEF inactivation on visually guided, delayed, and memory-guided saccades, using cryoloops implanted in the arcuate sulcus. While FEF inactivation produced the expected triad of contralateral saccadic deficits (increased reaction time, decreased accuracy and peak velocity) and performance errors (neglect or misdirected saccades), we also found consistent increases in reaction times of ipsiversive saccades in all three tasks. In addition, FEF inactivation did not increase the proportion of premature saccades to ipsilateral targets, as was predicted on the basis of pharmacological studies. Consistent with previous studies, greater deficits accompanied saccades toward extinguished visual cues. Our results attest to the functional contribution of the FEF to saccades in both directions. We speculate that the comparative effects of different inactivation techniques relate to the volume of inactivated tissue within the FEF. Larger inactivation volumes may reveal the functional contribution of more sparsely distributed neurons within the FEF, such as those related to ipsiversive saccades. Furthermore, while focal FEF inactivation may disinhibit the mirroring site in the other FEF, larger inactivation volumes may induce broad disinhibition in the other FEF that paradoxically prolongs oculomotor processing via increased competitive interactions

A Trial-by-Trial Window into Sensorimotor Transformations in the Human Motor Periphery.

UNLABELLED: The appearance of a novel visual stimulus generates a rapid stimulus-locked response (SLR) in the motor periphery within 100 ms of stimulus onset. Here, we recorded SLRs from an upper limb muscle while humans reached toward (pro-reach) or away (anti-reach) from a visual stimulus. The SLR on anti-reaches encoded the location of the visual stimulus rather than the movement goal. Further, SLR magnitude was attenuated when subjects reached away from rather than toward the visual stimulus. Remarkably, SLR magnitudes also correlated with reaction times on both pro-reaches and anti-reaches, but did so in opposite ways: larger SLRs preceded shorter latency pro-reaches but longer latency anti-reaches. Although converging evidence suggests that the SLR is relayed via a tectoreticulospinal pathway, our results show that task-related signals modulate visual signals feeding into this pathway. The SLR therefore provides a trial-by-trial window into how visual information is integrated with cognitive control in humans. SIGNIFICANCE STATEMENT: The presentation of a visual stimulus elicits a trial-by-trial stimulus-locked response (SLR) on the human limb within 100 ms. Here, we show that the SLR continues to reflect stimulus location even when subjects move in the opposite direction (an anti-reach). Remarkably, the attenuation of SLR magnitude reflected the cognitive control required to generate a correct anti-reach, with greater degrees of attenuation preceding shorter-latency anti-reaches and no attenuation preceding error trials. Our results are strikingly similar to neurophysiological recordings in the superior colliculus of nonhuman primates generating anti-saccades, implicating the tectoreticulospinal pathway. Measuring SLR magnitude therefore provides an unprecedented trial-by-trial opportunity to assess the influence of cognitive control on the initial processing of a visual stimulus in humans

Express arm responses appear bilaterally on upper-limb muscles in an arm choice reaching task

When required, humans can generate very short latency reaches toward visual targets, such as catching a falling cellphone. During such rapid reaches, express arm responses are the first wave of upper limb muscle recruitment, occurring ̴ 80–100 ms after target appearance. There is accumulating evidence that express arm responses arise from signaling along the tecto-reticulo-spinal tract, but the involvement of the reticulospinal tract has not been well studied. Since the reticulospinal tract projects bilaterally, we studied whether express arm responses would be generated bilaterally. Human participants (n = 14; 7 females) performed visually guided reaches in a modified emerging target paradigm where either arm could intercept the target. We recorded electromyographic activity bilaterally from the pectoralis major muscle. Our analysis focused on target locations where participants reached with the right arm on some trials, and the left arm on others. In support of the involvement of the reticulospinal tract, express arm responses persisted bilaterally regardless of which arm reached to the target. The latency and magnitude of the express arm response did not depend on whether the arm was chosen to reach or not. However, on the reaching arm, the magnitude of the express arm response was correlated to the level of anticipatory activity. The bilateral generation of express arm responses supports the involvement of the reticulospinal tract. We surmise that the correlation between anticipatory activity and the magnitude of express arm responses on the reaching arm arises from convergence of cortically derived signals with a parallel subcortical pathway mediating the express arm response. NEW & NOTEWORTHY Express arm responses have been proposed to arise from the tecto-reticulo-spinal tract originating within the superior colliculus, but the involvement of the reticulospinal tract has not been well studied. Here, we show these responses appear bilaterally in a task where either arm can reach to a newly appearing stimulus. Our results suggest that the most rapid visuomotor transformations for reaching are performed by a subcortical pathway

Stimulus-locked responses on human upper limb muscles and corrective reaches are preferentially evoked by low spatial frequencies

© 2019 Kozak et al. In situations requiring immediate action, humans can generate visually-guided responses at remarkably short latencies. Here, to better understand the visual attributes that best evoke such rapid responses, we recorded upper limb muscle activity while participants performed visually-guided reaches towards Gabor patches composed of differing spatial frequencies (SFs). We studied reaches initiated from a stable posture (experiment 1, a static condition), or during on-line reach corrections to an abruptly displaced target (experiment 2, a dynamic condition). In both experiments, we detail the latency and prevalence of stimulus-locked responses (SLRs), which are brief bursts of EMG activity that are time-locked to target presentation rather than movement onset. SLRs represent the first wave of EMG recruitment influenced by target presentation, and enable quantification of rapid visuomotor transformations. In both experiments, reach targets composed of low SFs elicited the shortest latency and most prevalent SLRs, with SLR latency increasing and SLR prevalence decreasing for reach targets composed of progressively higher SFs. SLRs could be evoked in either the static or dynamic condition, and when present in experiment 2, were associated with shorter latency and larger magnitude corrections. The results in experiment 2 are consistent with a linkage between the forces produced by SLRs and the earliest portion of on-line reach corrections. Overall, our results demonstrate that stimuli composed of low SFs preferentially evoke the most rapid visuomotor responses that, in the context of rapidly correcting an on-going reaching movement, are associated with earlier and larger on-line reach corrections

The behavioural and neurophysiological modulation of microsaccades in monkeys

Systematic modulations of microsaccades have been observed in humans during covert orienting. We show here that monkeys are a suitable model for studying the neurophysiology governing these modulations of microsaccades. Using various cue-target saccade tasks, we observed the effects of visual and auditory cues on microsaccades in monkeys. As in human studies, following visual cues there was an early bias in cue-congruent microsaccades followed by a later bias in cue-incongruent microsaccades. Following auditory cues there was a cue-incongruent bias in left cues only. In a separate experiment, we observed that brainstem omnipause neurons, which gate all saccades, also paused during microsaccade generation. Thus, we provide evidence that at least part of the same neurocircuitry governs both large saccades and microsaccades